The use of cocaine as a drug of abuse has markedly increased over the past few years. Associated with the well-known central nervous system stimulation effects is a marked elevation of systolic blood pressure and heart rate. Experimental literature has clearly demonstrated that repeated injections of animals with sympathomimetic agents will cause the development of arteriosclerotic lesions. Because cocaine is a sympathomimetic drug, the possibility exists that cocaine abuse is a potent risk factor in arteriogenesis. Preliminary studies in our laboratory using rabbits, have shown that daily use of cocaine can cause injury to the arterial wall. Rabbits that were injected intravenously for 14 days with cocaine exhibited mild to severe arteriosclerotic lesions. In the most severely diseased animals, the thoracic aorta was a stiff, dilated tube which contained confluent raised lesions projecting into the lumen. Histologically, there was fragmentation of the elastic lamella. Other evidence of severe aortic injury included increased rates of collagen and non-collagen protein synthesis. There was no histological or biochemical evidence of increased deposition of cholesterol in these diseased aortas. The changes caused by cocaine are similar to changes commonly observed in advanced stages of human arteriosclerosis. The present grant application is designed to further study the potential for cocaine to induce arteriosclerosis. Adult male rabbits will be administered cocaine intravenously for varying time periods. Their aortas will be carefully evaluated both histologically and biochemically. Rates of collagen and non-collagen protein synthetic activity will be used as a biochemical measure of aortic disease and injury. Aortic cholesterol, protein and DNA content will also be measured following cocaine administration. Experiments are proposed to establish the potential synergistic effect of cocaine with elevated serum cholesterol levels. The potential of these cocaine-induced lesions to regress when the drug is stopped will also be investigated. The hypothesis we are testing is that prolonged abuse of cocaine causes injury to the cardiovascular system resulting in arteriosclerotic lesion formation.